Gastrointestinal sphincters remain closed, maintaining a sustained pressure, and relax to allow the passage of a bolus. We will examine the mechanisms responsible for maintenance of the pressure barrier and its abolition during relaxation. 1) The tonus generated by the lower esophageal sphincter and the internal anal sphincter is myogenic as it is not abolished by the neural blocker tetrodotoxin. The mechanisms responsible for maintenance of this sustained tonic contraction have not been clarified. We will examine the role of calcium in phasic esophageal contraction and in maintenance of lower esophageal sphincter tonus. We will test the hypothesis that phasic contraction in the esophagus depends entirely on extracellular calcium, while lower esophageal sphincter tonus depends on intracellular calcium. This hypothesis may be relevant to understanding the mechanism of injury produced by repeated acid perfusion of the esophagus in acute experimental esophagitis. We will also test its relevance to chronic experimental esophagitis. 2) Relaxation is mediated by non-adrenergic non-cholinergic inhibitory neurons but the exact nature of the neurotransmitter is not known. We will examine the role of some neuropeptides in neurogenic relaxation. We and others have shown that VIP may be involved in neurogenic relaxation of the lower esophageal sphincter. Recently, we have shown that VIP may be responsible for relaxation of the internal anal sphincter. Other peptides of the VIP family (PHI, GRF) and a new peptide (NPY) will be tested to assess a possible role as participants in neurogenic relaxation as well as in the descending inhibition that preceeds peristaltic sweep. We will explore the mechanism by which these peptides produce inhibition of intestinal smooth muscle. In some tissues VIP and PHI activate adenylate cyclase and increase tissue content of cAMP, but a relationship between VIP and cAMP during LES relaxation has not been established. Furthermore, recent evidence suggests a possible role of cyclic GMP in smooth muscle relaxation. We propose to examine the role of cAMP and cGMP in LES relaxation and their relationships to these neuropeptides.